Overactive bladder (OAB) is a syndrome characterized by symptoms of “urgency with or without urge incontinence, usually with frequency and nocturia,” where urgency is defined as “the complaint of a sudden compelling desire to pass urine which is difficult to defer.” (Abrams et al., The standardization of terminology of lower urinary tract function: report from the Standardization Subcommittee of the International Continence Society, Neurourol. Urodyn. 21:167-178, 2002). OAB is one of several bladder diseases and may also be characterized by urge incontinence, detrusor instability, detrusor hyperreflexia, irritable bladder, spasmodic bladder, unstable bladder, incontinence—urge, or bladder spasms. OAB often presents itself as a strong, sudden need to urinate due to bladder spasms or contractions that can lead to frequent urination, in the daytime and at night, loss of urine (leaking) without meaning to urinate, and the sudden and urgent need to urinate (urinary urgency). Proper bladder control, therefore, requires the lower urinary tract and nervous system to work together to allow for the feeling and ability to respond to the urge to urinate at appropriate intervals, while minimizing leaking and urinary urgency.
The process of urination involves two phases: (i) filling and storage; and (ii) emptying. For the bladder to fill and store urine, the sphincter muscle (which controls the flow of urine out of the body) and bladder wall muscle (detrusor) must work together under nervous system control. During the filling and storage phase, the nervous system provides signals instructing the bladder to fill, and the bladder stretches so it can hold more urine. A typical human bladder holds anywhere from about 350 milliliters (ml) to about 550 ml of urine. A healthy adult human may, for example, feel the need to urinate when there is about 200 ml or more of urine in the bladder. The nervous system then provides signals instructing the bladder to empty. During the emptying phase, the detrusor muscle contracts and the sphincter muscle relaxes, working together to force urine out of the bladder, through the urinary tract, and out of the body.
Proper bladder control and control over urination frequency is part of normal childhood development. An infant's bladder automatically contracts when a certain amount of urine has collected in the bladder. As the child grows older and learns to control urination, part of the brain (cerebral cortex) helps prevent bladder muscle contractions. This allows for proper bladder control to delay urination until the child is ready to use the bathroom.
Disease states and advanced age, however, can alter a person's ability to control the bladder and urination frequency. The prevalence of OAB increases with age and is difficult to determine owing to the attached stigma, which may prevent patients from seeking medical care. OAB is estimated to affect 17% of the adult population in the United States and is ranked among the ten most common medical conditions. (Milson et al., The prevalence of overactive bladder, Am. J. Manag. Care 6 (11 suppl.):5565-573, 2000; Milson et al., How widespread are the symptoms of an overactive bladder and how are they managed? A population-based prevalence study, Br. J. Urol. Int. 87:760-66, 2001).
For example, a person's bladder may contract too often from nervous system (neurological) stimulation or bladder irritation, or a person suffering from OAB may leak urine because the bladder muscles contract at the wrong times. Often these contractions occur regardless of how much urine is in the bladder. OAB may have a variety of etiologies, some of which may not be true underlying causes of the disorder but nonetheless contribute to presentation of symptoms, including but not limited to bladder cancer, bladder inflammation, bladder outlet obstruction, bladder stones, infection, nervous system diseases (such as multiple sclerosis), nervous system injuries (such as stroke), and in men, urge incontinence also may be due to bladder changes caused by benign prostatic hypertrophy (BPH) or bladder outlet obstruction from an enlarged prostate. In many other cases, however, no cause can be found for OAB.
There are three main treatment approaches for OAB: medication, retraining, and surgery. Current medications used to treat OAB may relax bladder contractions to help improve bladder function. There are several types of medications that may be used alone or together. Anticholinergic medicines are reported to help relax the muscles of the bladder. These include oxybutynin (Oxytrol®, Ditropan®), tolterodine (Detrol®), darifenacin (Enablex®), trospium (Sanctura®), solifenacin (Vesicare®), and fesoterodine (Toviaz®). All of these anticholinergic medicines are competitive muscarinic receptor antagonists, and muscarinic receptors play an important role in several major cholinergically mediated functions, including contractions of urinary bladder smooth muscle and stimulation of salivary secretion. A relatively high incidence of dry mouth and, to a lesser extent, constipation is known as a potentially limiting side effect of anti-muscarinic therapy in humans. In addition, one significant contraindication, however, is that people with narrow-angle glaucoma cannot use anti-muscarinic medications. Flavoxate (Urispas) is a drug that calms muscle spasms. Studies have shown, however, that flavoxate is not always effective at controlling symptoms of urge incontinence. Tricyclic antidepressants (imipramine, doxepin) have also been used to treat urge incontinence because of their ability to “paralyze” the bladder smooth muscle. Reported possible side effects include: blurred vision, dizziness, dry mouth, fatigue, insomnia, and nausea. Mirabegron (Myrbetriq®) is a beta-3 adrenergic agonist that relaxes the detrusor smooth muscle during the storage phase of the urinary bladder fill-void cycle. Hypertension is a significant side effect of mirabegron, which also demonstrated very limited efficacy in human clinical trials.
All of these medicines have demonstrated limited efficacy, and not all patients achieve acceptable therapeutic responses, resulting in a significant unmet medical need. These treatments are also associated with therapy limiting side effects, notably dry mouth, dry eyes, blurred vision, constipation, hypertension, and cognitive dysfunction. The majority of available medications are metabolized by the cytochrome P450 pathway potentially leading to drug-drug interactions, especially in the elderly where OAB is most common and in whom poly pharmacy is also common. The limited efficacy and significant incidence of adverse effects diminish the usefulness of these drugs; often patients stop taking these medications altogether. More than 70% of patients do not continue therapy beyond nine months. (NDC Health Corporation: Persistency Data, Atlanta NDC Health Corporation, 2000). Of those remaining on treatment, some patients take less than the optimal dosage to avoid the side effects. Alternative OAB medications are needed with different safety, metabolic, tolerability, and efficacy profiles. Mecamylamine (N,2,3,3-tetramethylbicyclo[2.2.1]heptan-2-amine hydrochloride), was developed and characterized by Merck & Co., Inc., as a ganglionic blocker with clinically significant hypotensive actions (Stone et al., Chemistry and structure-activity relationships of mecamylamine and derivatives, J. Med. Pharm. Chem., 5(4):665-690, 1962). Mecamylamine was sold under the tradename Inversine®. Depending on preferred naming convention, the chemical name for mecamylamine may also be N,2,3,3-tetramethylnorbornan-2-amine. Mecamylamine exists as a racemic mixture of enantiomers and can be obtained according to the methods and processes described in U.S. Pat. No. 5,986,142, incorporated herein by reference for its teaching regarding methods of producing mecamylamine.
Unique characteristics of mecamylamine, including oral efficacy for treating hypertension, rapid onset, long duration of action, and nearly complete absorption from the gastrointestinal tract, made the drug a more desirable alternative to the existing ganglionic blockers. The average total daily dose of Inversine® (mecamylamine hydrochloride) used to treat high blood pressure was 25 mg, usually administered in three divided doses. The safety/tolerability profile of mecamylamine in humans has been established during decades of clinical use as an antihypertensive agent. The most common adverse reactions to the marketed drug include constipation, orthostatic dizziness, urinary retention, and blurred vision.
Bladder contraction is primarily controlled by the autonomic nervous system with input from higher centers. Ganglion blockers, such as racemic mecamylamine, decrease bladder contraction and lead to urinary retention. Kaplan et al. reported that racemic Inversine® doses of 2.5 mg BID produced changes in bladder contractility in spinal cord injury subjects. (Kaplan et al., Reduction of bladder contractility after alpha-adrenergic blockade and after ganglionic blockade, Acta Neurol. Scandinav. 59, 172-77, 1979). However, Kaplan et al. also reported that racemic mecamylamine administration resulted in a decrease in bladder electric potential (amplitude of contraction), which would indicate incomplete bladder emptying.
U.S. Pat. No. 7,101,916, herein incorporated by reference, provides for a pharmaceutical composition that includes a therapeutically effective amount of exo-S-mecamylamine or a pharmaceutically acceptable salt thereof, substantially free of exo-R-mecamylamine, in combination with a pharmaceutically acceptable carrier, wherein the pharmaceutical composition is characterized by a higher overall therapeutic index than a substantially similar pharmaceutical composition comprising exo-R-mecamylamine substantially free of exo-5-mecamylamine. The medical conditions disclosed therein include but are not limited to substance addiction (involving nicotine, cocaine, alcohol, amphetamine, opiate, other psychostimulant and a combination thereof), aiding smoking cessation, treating weight gain associated with smoking cessation, hypertension, hypertensive crisis, herpes type I and II, Tourette's Syndrome and other tremors, cancer (such as small cell lung cancer), atherogenic profile, neuropsychiatric disorders (such as bipolar disorder, depression, anxiety disorder, panic disorder, schizophrenia, seizure disorders, Parkinson's disease and attention deficit hyperactivity disorder), chronic fatigue syndrome, Crohn's disease, autonomic dysreflexia, and spasmogenic intestinal disorders. OAB is not described or disclosed in U.S. Pat. No. 7,101,916. The patent discloses that exo-5-mecamylamine may be administered intravenously, intramuscularly, transdermally, intrathecally, orally or by bolus injection. The dosage of exo-5-mecamylamine for treating the identified diseases is described in a range of about 0.5 mg to about 1000 mg, depending on dosage form, and exo-5-mecamylamine may be administered one to four times per day. Examples include a dose of about 2.5 mg per day for adults with drug-resistant Tourette's Syndrome and 1 mg per day or less for a small child with mild ADHD.
Purified exo-5-mecamylamine and exo-R-mecamylamine can be obtained according to methods discussed in U.S. Pat. No. 7,101,916, and references cited therein, also incorporated herein by reference for their teaching regarding the production of purified mecamylamine enantiomers. Exo-S-mecamylamine may also be referred to as dexmecamylamine, S-mecamylamine, TC-5214, or (S)—N,2,3,3-tetramethylnorbornan-2-amine, and includes a pharmaceutically acceptable salt thereof.
Dexmecamylamine is a use-dependent potent inhibitor of the α3 nicotinic receptor subtype (e.g., α3β2 and α3β4). Such receptors are expressed in the urothelium and regulate bladder smooth muscle contraction. (Beckel et al., Expression of functional nicotinic acetylcholine receptors in rat urinary bladder epithelial cells, Am. J. Physiol. Renal Physiol. 290:F103-110, 2006). Dexmecamylamine, however, has not been studied previously in a rat model related to urinary function.
There remains a need for effective treatment of OAB, with specific focus toward symptomatic relief, having an improved side effect and tolerability profile.